Experimenting With Drugs
The next step to therapy comes in finding the drugs that will work
just as specifically, fingerprint by fingerprint. That is the work
of Harlan Waksal, whose biotech company, ImClone Systems, has been
the focus of controversy this year after seeking FDA approval for
a promising anti-colon cancer drug.

A native of Dayton, Ohio, Waksal, a pathologist, double-majored
in biology and philosophy at Oberlin, followed by medical school
at Tufts University. He quickly found himself itching to do more.
"I wanted to do something that would have a greater potential
benefit," he explains. "That comes out of a philosophy
I gained at Oberlin."

In 1984 he partnered with his brother, Samuel, who
had a PhD in immunology, to launch ImClone Systems in Manhattan.
With Harlan as its chief operating officer and Samuel trying to
woo venture capitalists, the pair struggled at first with their
mission: to research and develop experimental drugs relating to
the immune system.

With truckloads of persistence and a bit of luck,
the Waksals obtained a novel drug that represented a new breed of
specific anti-cancer agent. In 1994, ImClone researchers began injecting
the drug C225--now dubbed Erbitux--into their first cancer patients,
people who had reached the last stages of colon cancer after failing
two other types of chemotherapy.

Erbitux, says Waksal, targets the cells of solid tumors
by gumming up the receiver of the "on" signal. Normally,
he explains, cell division is regulated by two opposing systems:
"on" and "off."

"Inducing a cell to divide is a lot like getting
your car to go," Treichel says. "You need to give it a
series of "on" signals. A driver must key the ignition,
put the car in gear, and press the accelerator--the "on"
signals. But to drive a car, one must also release the parking brake,
an "off" signal. The balance between the on-off system
in cells is crucial.

"Cancer cells violate that balance," she
adds. "They divide according to their own agenda."

The reason has to do with mutations. Cells turn cancerous
in a cumulative fashion. A person might be born with or acquire
a mutation in one or two "off" signals. The cell is not
yet cancerous, but simply more prone to divide. Over time, a person's
cells might accumulate even more mutations, perhaps through lifestyle
choices. Smoking might cause cells to gain genetic alterations in
the remaining "off" signals, in essence killing the brakes
on cell division.

Cancer researchers have spent decades trying to come
up with drugs that either reapply the brakes or force wayward cells
to commit suicide in a biochemical process known as apoptosis. But
ImClone researchers had another idea: to wipe out the "on"
receiver that tells the cancer cell to divide wantonly, says Waksal.
Erbitux targets the "on" receiver called the epidermal
growth factor receptor, which is found in abundance in many solid
tumors such as those of colon, head, and neck cancers. Tumor cells
actually produce more of this receptor compared to normal cells
because cancer cells want to fuel their own reproduction. "With
Erbitux, we are reintroducing a check to cell division," Waksal
says.

Early studies seemed to bolster Waksal's case. In
October 1999, ImClone launched a study of 125 patients with colon
cancer who had failed treatment with a chemotherapy agent called
Irinotecan. Erbitux, when given intravenously in combination with
Irinotecan, shrunk the tumors in 27 patients by half; in the oncology
world, that's a 22.5 percent response rate. A later clinical trial
of 40 patients with pancreatic cancer also turned up promising results.
The tumors in five patients shrunk by half, and the cancers in 16
others either stalled in growth or showed some response to the drug
when given in combination with chemotherapy.

This seemed unusually promising for such sick patients,
especially for those with pancreatic cancer which is typically untreatable,
but the FDA in January refused to consider ImClone's application
to sell the drug. Reportedly, the agency was critical of some aspects
of the clinical trials--including whether enough patients had been
tested and if the original patients were actually as sick as reported.
Also questioned was a lack of information on the drug's side effects.
Still, the Waksal brothers and other researchers are confident that
the FDA's concerns will be addressed and that the application will
be accepted for review within the year. Trials with similar drugs
are under way with pharmaceutical giants AstraZeneca and Genentech.

"This is my crystal ball," says Waksal.
"I hope we can turn cancer into a chronic type of disease where
we can keep people alive with a good quality of life, in spite of
the problems." This would be far better news than an imminent
death sentence to patients with aggressive cancers or those in later
stages of spreading.